The hemochromatosis gene (HFE) has been involved in the etiology of type 2 diabetes mellitus and investigated in numerous epidemiologic studies. The current meta-analysis was conducted to evaluate the gene-disease association in relevant studies. Electronic literature search was performed on June 18, 2011, from databases of PubMed/MEDLINE, EMBASE, and HuGE Navigator. Articles were inspected by 2 authors independently, and data were extracted by identical extraction form. A total of 5,528 type 2 diabetes cases and 6,920 controls in relation to HFE polymorphisms (a cysteine to tyrosine substitution at amino acid position 282 (C282Y) and a histidine to aspartate substitution at amino acid position 63 (H63D)) were included in the meta-analysis (1997-2011). A fixed- or random-effect model was used to calculate the pooled odds ratios based on the results from the heterogeneity tests. An increased odds ratio for type 2 diabetes mellitus was observed in persons carrying a D allele at the H63D polymorphism compared with those with an H allele (odds ratio (OR) = 1.21, 95% confidence interval (CI): 1.03, 1.41; P = 0.02). Moreover, carriers of a D allele had a modestly increased risk compared with persons with the wild genotype (OR = 1.12, 95% CI: 1.00, 1.25; P = 0.04). The C282Y variant was not significantly associated with diabetes risk. In summary, persons with a D allele may have a moderately increased risk of type 2 diabetes mellitus.